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Menthol via Lipase Resolution

Researchers at CSIR Bio/Chemtek have developed a process
to produce l-menthol from the readily available raw material
m-cresol.

Alkylation of m-cresol generates thymol. Hydrogenation of
thymol yields four pairs of racemic diastereomers: menthol,
isomenthol, neomenthol, and neoisomenthol. Acylation of this
mixture using a stereoselective lipase yields l-menthyl
acetate in at least 96% enantiomeric excess (ee). l-Menthyl
acetate is separated from the unreacted isomers by
distillation. Hydrolysis yields (-)-menthol. The enzymatic
resolution has been demonstrated in a continuous process at
1 kg per hour. Enzyme activity is retained even after 2,000
hours of operation. Furthermore, isomerization/racemization
of the unreacted isomers regenerates the original mixture of
diastereomers, which is routed again to enzyme resolution.
Over several cycles, thymol is almost fully converted to
l-menthol. This process is the subject of a 2002 patent
assigned to AECI which is available for download below.

Similarly, Haarmaan & Reimer was recently (July 17,
2002) issued a patent for the resolution of racemic menthol
esters (Benzoate, acetate, etc.) using lipases (e.g.,
Candida rugosa) that provides (-)-menthol with essentially
100% enantioselectivity. This patent is also available for
download below.

While neither the AECI or H&R process have yet been
commercialized, these routes are certainly of high
interest.

It should be noted that as early as 1968, workers at
Takasago had shown that (-)-menthol could be selectively
produced by the hydrolysis of racemic esters of menthol
using an enzyme carboxylic acid
hydrolase.7